Mephenesin acetylsalicylate



United States Patent 3,461,152 MEPHENESIN ACETYLSALICYLATE Joseph Pouget, Paris, France, assignor to Droit et Pharmacie, Paris, France, a corporation of France No Drawing. Continuation of application Ser. No.

405,574, Oct. 21, 1964. This application May 6,

1968, Ser. No. 727,026

Claims priority, application france, Oct. 24, 1963,

Int. Cl. C07c 69 86; A61k 27/00 U.S. Cl. 260474 1 Claim ABSTRACT OF THE DISCLOSURE An analgesic anticontracturant and local anesthetic for superficial application in the region of the contraindication, composed of or containing mephenesin acetylsalicylate.

It has now been discovered that this new composition of matter, which can be produced by esterifying mephenesin with acetylsalicylic acid advantageously by conventional pyridinic acylation. Thus, when pyridinic acylation of mephenesin is carried out with the chloride of acetylsalicyclic acid (aspirin chloride), it is possible to obtain mephenesin acetylsalicylate as a distinct compound. As previously indicated, this compound which has a calculated molecular weight of 344.3 and a structural formula determined from its method of production is essentially as follows:

From its structural formula, the mephenesin acetylsalicylate or (methyl-2, phenoxy)-3-propanediol-l,2, or as the acetylsalicylate of 3-ortho-toloxy-1,2-propanediol. Since mephenesin is sometimes referred to as orthocresyl-alphaglycerol ether, the new compound can also be designated as the acetylsalicylate of this latter substance. In general, the compound has been found to be highly effective as a local anesthetic and as an anticontracturant capable of relaxing muscular tension, strain, irritation and contraction. The product, when prepared by pyridinic acylation of mephenesin acetylsalicylic chloride and washing with hydrochloric acid is found to have a boiling point at 4 mm. Hg of 228 to 235 C. and at 8 mm. Hg of 245 to 255 C. Tests confirm the existence of the acetylsalicylic fragment and the characteristic parts of the mephenesin fragment upon degradation of the product. The pale-yellow ice oily compound is very slightly soluble in water, highly soluble in lower alcohols (ethanol), ethers (ethyl ether), acetone, ethyl acetate, benzene, toluene and chloroform, while alcohol and acetone solutions of the compound precipitate it when water is added. In the purified state, the product is believed to have a boiling point at 4 mm. Hg of 232 to 234 C.

The product possesses pharmacological properties which in some respects are similar to those of aspirin although it is essentially more stable than aspirin in the presence of water and moisture. It is highly effective as a local anesthetic and analgesic for the treatment of human contractions and irritations of the type arising from physical strain, fatigue and the like. The compound is applied superficially in the form of a lotion, cream, emulsion, suspension or other composition and can be present in an amount ranging between substantially 1 and 10 parts by weight per 100 parts by weight, i.e. 1 to 10% by weight, of the vehicle which may contain parafiin oils, petroleum jelly, polyethylene glycols or other materials suitable for superficial application.

The invention will become more readily apparent from the following specific examples of the method of producing the new compound constituting the subject matter of the present invention and the additional examples of therapeutic applications of the compound given below.

EXAMPLE Preparation of reactant Aspirin chloride (acetylsalicylic chloride) is obtained by treating acetylsalicylic acid (aspirin-C H O C H CO H) with thionyl chloride and distilling the mixture. A thoroughly dried l-liter flask is used in the reaction vessel into which 180 grams (1 mole) of acetylsalicylic acid and 260 grams (2 moles) of thionyl chloride are introduced. The mixture is refluxed with gentle heating until all of the acetylsalicylic acid goes into solution, i.e. a period of about 45 minutes. The result is a light-yellow clear liquid. Residual and excess thionyl chloride is distilled in vacuo by heating in a water or mud bath. It :must be noted that throughout the preparation of the aspirin chloride, moistureand water-free conditions must prevail to prevent hydrolysis of the thionyl chloride.

When residual thionyl chloride is distilled off, approximately to grams are obtained which may be used without further purification as a raw material for the production of further batches of the acetylsalicylic chloride. The latter compound is found to be highly unstable at ambient pressures when heated and can be purified by distillation in vacuo, retaining the fraction passing over at 131 to 134 C. at 7 mm. Hg; to 144 C. at 11 mm. Hg; and 180 to 184 C. at 28 mm. Hg. Decomposition results at the boiling point at higher pressures. Approximately to grams of the slightly yellowtinted liquid (acetylsalicyclic acid) is obtained (i.e. about 80 to 90% of theoretical yield). Since it is essential for the subsequent reaction that the acetylsalicyclic chloride be highly pure, it is desirable that only an intermediate portion of the distillate be retained with the initial portion and final portion of the distillation being combined with subsequent batches for redistillation. The paleness of the color is an excellent indication of the suitability of the retained fraction. The acetylsalicylic chloride can be stored in a ground-glass-stoppered and thoroughly dry vessel although it is preferred to use it as soon as possible.

Preparation of mephenesin acetylsalicylate 10.8 grams (0.06 mole) of mephenesin is dissolved in 40 ml. of pyridine and the mixture chilled in ice. Into the cooled solution the acetylsalicylic chloride is added dropby-drop with agitation until 12 grams (0.06 mole) of the aspirin chloride is added. At the conclusion of this addition, the mixture is permitted to stand for one hour under refrigeration and then for an additional hour at ambient temperature. Subsequently, 500 ml. of 10% aqueous hydrochloric-acid solution is added slowly and with agitation. An oily layer separates from the reaction mixture and is removed by decantation whereupon the oily layer is washed by shaking it three times with 50 ml. quantities of the hydrochloric acid. The product is heated in vacuo and, after elimination of water, the fraction coming over at 228 to 235 C. at 4 mm. Hg or at 245 to 255 C. at 8 mm. Hg is retained. The yield is about 60% of theoretical of mephenesin acetylsalicylate.

Elemental analysis of the product gave the following results: carbon calculated 66.27%, found 66.01% and 66.86% in two preparations; hydrogen calculated 5.85%, found 6% and 5.82% in the two preparations; and oxygen, calculated 27.87% and found 28.14% and 27.99%, all percents by weight. The molecular weight of the compound was determined by saponification and was found to be 325.5, but calculated as 344.3. The structure of the compound was determined by degradation techniques in which 0.3 gram of the product was dissolved in ml. of ethanol and a tablet of sodium carbonate added. After boiling for several minutes, the mixture was neutralized and a part of the solution gave an intense violet color, indicating the presence of salicylic acid, when treated with ferric chloride. Another part of the neutralized solution was acidified with 1 ml. of sulfuric acid and brought to the boiling point whereupon an odor of ethyl acetate was detected, indicating that acetic acid was a decomposition product of the neutralization of the mephenesin acetylsalicylate.

As previously indicated, the new product is a lightyellow oily liquid whose boiling point, after redistillation in vacuo, is 232 to 234 C. at 4 mm. Hg and has a stability far exceeding that of aspirin in the presence of moisture, although the hydrolysis curves of aspirin and the mephenesin have similar appearances. After beginning rapidly, the rate of hydrolysis attains a level at which it further takes place only very slowly. From a quantitative point of view, however, the mephenesin acetyslalicylate is much more stable than aspirin in aqueous media and in alcoholic solutions. The product can be employed as the hydrogen chloride in pharmacological preparations where this resistance to hydrolysis is important.

The following specific examples of actual clinical uses of the product show its effectiveness as a human medicament for the relaxation of muscular contractions and as a local analgesic in the treatment of cramp and fatigue contractions, myalgic muscular disorders, strain lumbagos, lumbar strain, stiff neck, strained back, sprains, and the like.

EXAMPLE A A 23 year old male suffering from muscular pain at the scapula as a result of intense efforts in athletics is treated four times daily with a lotion containing mephenesin acetlysalicylate as produced above. A conventional body lotion was employed with the mephenesin acetylsalicylate added in approximately 5 parts by weight to 100 parts of the composition. The pain and irritation disappeared completely. Noticeable relief was obtained after several applications. The lotion consists essentially of 5 parts by weight mephenesin acetylsalicylate, 10 parts by weight of paraflin oil and suflicient petroleum jelly to bring the lotion to 100 parts.

EXAMPLE B A 38 year old male suffering from lumbago obstructions of flection of the spinal column was treated four times daily by superficially rubbing with the lotion de scribed above. After four days the pain disappeared completely and flection of the vertebral column became possible. The best results are obtained when the mephenesin acetylsalicylate was incorporated in a lotion, gel, linament or cream in a conventional vehicle and applied with massage and rubbing. Similar results were obtained when instead of the lotion of Example A, anhydrous cream consisting of 5 parts by weight mephenesin acetylsalicylate and parts by weight polyethylene glycol (M.W. 1500) was used. A cream emulsion having similar properties was produced by mixing 5 parts by weight mephenesin acetylsalicylate, 19.5 parts by weight propylene glycol monostearate, 1.5 parts by weight petroleum oil, 3 parts by weight petroleum jelly, 0.5 part by weight methyl p-hydroxy benezoate, the balance Water to make parts of the composition.

I claim:

1. Mephenesin acetlysalicylate having a molecular weight of 344.3, the empirical formula: C H O and having the structure formula:

LORRAINE A. WEINBERGER, Primary Examiner D. STENZEL, Assistant Examiner US. Cl. X.R. 424-230 

